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Synthetic Technologies of Pharmaceutical Substances

Andrzej Kutner 

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland


Pharmaceutical substances represent nowadays one the most advanced and complicated technological products. In this lecture an attempt will be made to outline the specific features that differ these substances from all other synthetic compounds. The most common convergent approach to the synthesis of pharmaceutical substances will be discussed on a number of examples from several chemical classes. The convergent synthesis allows not only for the preparation of a series of structurally related known and new analogs from the same advanced intermediates, but also provides a way to construct the target molecule at very last stages of synthesis. This way a more efficient separation might be obtained of final product from the substrates that opens a way to the synthetic product of pharmaceutical quality. Selection of a synthetic route for pharmaceutical substance is based on several criteria, typical for all chemical compounds, like the efficiency of chemical synthesis (yields and number of steps, extreme conditions etc.) but also on several other specific factors. One of these is the selection of synthetic methods that not only do not infringe the intellectual property rights of other researchers but also that can be claimed by new patent applications. Other important criteria include the commercial availability of raw materials of reliable quality and the feasibility to purify the synthetic product to the pharmaceutical grade. In order to turn the synthetic method into a technology it is crucial to acquire initially a sufficient understanding of the reaction to define the critical parameters of the process and the design space. Chemical and economical optimization of these parameters by statistical methods, like Fractional Factorial Design, often results in much higher yields of the process, less extreme conditions and more efficient use of materials, reaction volume, timing and equipment. In a pharmaceutical synthesis it is important not only to synthesize the final product of the top purity but also obtain the material that is suitable for the further pharmaceutical formulation. Therefore what also matters are the physicochemical, solid state and surface properties of the product, like the right polymorphic form and the convenient particle size and shape distribution. In the summary, the pharmaceutical technology might be considered as a validated chemical process with identified and optimized critical parameters. The process that is fully controlled by validated analytical methods that are used to define the quality also of raw materials and advanced intermediates, in order to prepare repeatedly the final product of pharmaceutical grade, suitable for further pharmaceutical formulation.

1. S. Randzio, A. Kutner, Metastability and Instability of Organic Crystalline Substances, J.Phys. Chem. 112, 1435-1444 (2008).

2. M. Chodyński, M. Krupa, K. Krajewski, M. Kubiszewski, K. Trzcinska, A. Kutner, P-388752, 2009.                                           


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Related papers

Presentation: Invited oral at VII Multidyscyplinarna Konferencja Nauki o Leku, by Andrzej Kutner
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-04-07 08:56
Revised:   2010-04-07 08:56